Palmitate-induced C/EBP homologous protein activation leads to NF-κB-mediated increase in BACE1 activity and amyloid beta genesis

Gurdeep Marwarha, Jared Schommer, Jonah Lund, Trevor Schommer, Othman Ghribi

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The etiology of Alzheimer's disease (AD) is egregiously comprehended, but epidemiological studies have posited that diets rich in the saturated fatty acid palmitic acid (palmitate) are a significant risk factor. The production and accumulation of amyloid beta peptide (Aβ) is considered the core pathological molecular event in the pathogenesis of AD. The rate-limiting step in Aβ genesis from amyloid-β precursor protein (AβPP) is catalyzed by the enzyme β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the expression and enzymatic activity of which is significantly up-regulated in the AD brain. In this study, we determined the molecular mechanisms that potentially underlie the palmitate-induced up-regulation in BACE1 expression and augmented Aβ production. We demonstrate that a palmitate-enriched diet and exogenous palmitate treatment evoke an increase in BACE1 expression and activity leading to enhanced Aβ genesis in the mouse brain and SH-SY5Y-APP S we cells, respectively, through the activation of the transcription factor NF-κB. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays revealed that palmitate enhances BACE1 expression by increasing the binding of NF-κB in the BACE1 promoter followed by an enhancement in the transactivation of the BACE1 promoter. Elucidation and delineation of upstream molecular events unveiled a critical role of the endoplasmic reticulum stress-associated transcription factor, C/EBP homologous protein (CHOP) in the palmitate-induced NF-κB activation, as CHOP knock-down cells and Chop −/− mice do not exhibit the same degree of NF-κB activation in response to the palmitate challenge. Our study delineates a novel CHOP-NF-κB signaling pathway that mediates palmitate-induced up-regulation of BACE1 expression and Aβ genesis. (Figure presented.).

Original languageEnglish (US)
Pages (from-to)761-779
Number of pages19
JournalJournal of Neurochemistry
Volume144
Issue number6
DOIs
StatePublished - Mar 2018
Externally publishedYes

Keywords

  • Alzheimer's disease
  • C/EBP homologous protein
  • endoplasmic reticulum stress
  • nuclear factor of kappa-light-polypeptide gene enhancer of activated B cells
  • palmitic acid
  • β-site APP cleaving enzyme 1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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